EP3458059A1 - Irinotécan nanoliposomal utilisé dans le traitement du cancer bronchique à petites cellules - Google Patents

Irinotécan nanoliposomal utilisé dans le traitement du cancer bronchique à petites cellules

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Publication number
EP3458059A1
EP3458059A1 EP17734449.6A EP17734449A EP3458059A1 EP 3458059 A1 EP3458059 A1 EP 3458059A1 EP 17734449 A EP17734449 A EP 17734449A EP 3458059 A1 EP3458059 A1 EP 3458059A1
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Prior art keywords
irinotecan
sclc
human patient
administration
dose
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EP17734449.6A
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German (de)
English (en)
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Bambang ADIWIJAYA
Jonathan Basil Fitzgerald
Helen Lee
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Ipsen Biopharm Ltd
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Ipsen Biopharm Ltd
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Publication of EP3458059A1 publication Critical patent/EP3458059A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof

Definitions

  • Provisional Application No.62/370,449 (filed August 3, 2016), U.S. Provisional Application No. 62/394,870 (filed September 15, 2016), U.S. Provisional Application No. 62/414,050 (filed October 28, 2016), U.S. Provisional Application No. 62/415,821 (filed November 1, 2016), U.S. Provisional Application No. 62/422,807 (filed November 16, 2016), U.S.
  • Provisional Application No. 62/433,925 (filed December 14, 2016), U.S. Provisional Application No. 62/455,823 (filed February 7, 2017), and U.S. Provisional Application No. 62/474,661 (filed March 22, 2017), each of which is incorporated herein by reference in its entirety.
  • the present invention relates to the treatment of patients diagnosed with small cell lung cancer (SCLC), including patients with SCLC disease progression after treatment with a platinum-based therapy.
  • SCLC small cell lung cancer
  • SCLC Small-cell lung cancer
  • Initial (first line) treatment of SCLC can include administration of a platinum- based therapy such as 4-6 treatment cycles of cisplatin or carboplatin, in combination with etoposide or irinotecan.
  • Current subsequent (second line) therapy upon SCLC disease progression (after first line therapy) has been reported to provide overall survival of about 7.7 months (sensitive patients) and 5.4 months (refractory patients) based on (Owonikoko, TK, et al., J Thorac Oncol. 2012 May;7(5):866-72).
  • topotecan e.g., HYCAMTIN, topotecan hydrochloride injection
  • HYCAMTIN topotecan hydrochloride injection
  • second line SCLC treatment with topotecan at 1.5 mg/m 2 administered on days 1-5 once in a three (3)-week treatment cycle provided overall response rates of about 7-24%, progression free survival (PFS) of about 3.1-3.7 months, and overall survival (OS) of 5.0-8.9 months (accompanied by grade 3 or greater neutropenia rates of 28-88%) and grade 3 or greater diarrhea of less than about 5%) (PMIDs 16481389, 17135646, 17513814, 9164222, 10080612, 25385727).
  • Another reported SCLC second line therapy is the administration of non-liposomal irinotecan at 300 mg/m 2 once every three (3) weeks, providing mixed overall response rates of 0-33%>, PFS of 1.7-2.8 months, and OS of 4.6-6.9 months (accompanied by grade 3 or greater neutropenia rates of 21-23% and grade 3 or greater diarrhea of less than about 0-13%) (PMID 19100647, 1321891).
  • Irinotecan is an active agent in the treatment of SCLC (e.g., listed in NCCN and ESMO guidelines) but it is not approved in the US or EU. Furthermore, it failed in a PHASE III registration-directed study in combination with a platinum in first line SCLC (PMID: 16648503). No targeted treatment has been successful to date in significantly improving the outcome of patients. The research of novel treatments for this disease is therefore urgently needed.
  • the present disclosure provides methods of treating patients with small cell lung cancer after disease progression following platinum-based therapy, by administering a therapeutically effective amount of liposomal irinotecan.
  • a liposomal irinotecan such as MM-398 (ONIVYDE)
  • the liposomal irinotecan can be administered to patients diagnosed with SCLC disease progression on or after first-line platinum based chemotherapy (carboplatin or cisplatin), immunotherapy, and/ or chemo-radiation including platinum-based chemotherapy for treatment of limited or extensive stage SCLC.
  • a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC can be treated once every two weeks with an antineoplastic therapy consisting of a single dose of 90 mg/m 2 of irinotecan (free base) encapsulated in irinotecan liposomes.
  • SCLC small cell lung cancer
  • a human patient who is known to be homozygous for the UGT1A1 *28 allele and is diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC can be treated with an antineoplastic therapy consisting of a single reduced dose (e.g., 50-70 mg/m 2 , including 50 mg/m 2 or 70 mg/m 2 ) of irinotecan (free base) encapsulated in liposomes, administered once every two weeks.
  • SCLC small cell lung cancer
  • a human patient who has previously experienced a Grade 3+ adverse event while or after receiving liposomal irinotecan after being diagnosed with small cell lung cancer (SCLC), and after disease progression following platinum-based therapy for the SCLC can be treated with an antineoplastic therapy consisting of a single reduced dose (e.g., 50-70 mg/m 2 , including 50 mg/m 2 or 70 mg/m 2 ) of irinotecan (free base) encapsulated in liposomes, administered once every two weeks.
  • SCLC small cell lung cancer
  • the liposomal irinotecan can be a pharmaceutically acceptable liposome formulation of irinotecan, comprising irinotecan in a delivery form having a diameter of about 100 nm, such as a liposomal irinotecan (Example 1).
  • a liposomal irinotecan (Example 1).
  • Various suitable liposomal irinotecan preparations can be manufactured as disclosed herein (Example 8).
  • the liposomal irinotecan is the product MM-398 (ONIVYDE®) (Example 9). In the present disclosure MM-398 is used interchangeably with MM-398 liposomal irinotecan.
  • Figure 1 is a graph showing the drug sensitivity data to SN-38 from the Sanger database were plotted for SCLC, gastrointestinal, and pancreatic cancer cell lines
  • Figures 2A and 2B are kinetic growth curves of DMS114 and NCI-H1048 SCLC cell lines acquired on an Incucyte instrument over 88 hours at various SN-38 concentrations
  • Figure 3 is a graph showing the anti-tumor activity of MM-398 in the DMS114 xenograft model of SCLC. MM-398 was administered IV at 10 or 20 mg/kg irinotecan hydrochloride trihydrate starting on Day 23 and given weekly for 4 weeks and compared to saline control (black circles).
  • Figure 4 is a Kaplan-Meier Plot of overall survival by quartiles of unencapsulated SN-38 (uSN38) time above threshold in the MM-398+5FU/LV arm of NAPOLI-1.
  • Q1-Q4 represent the quartiles of uSN38 time above threshold.
  • Ql represents the shortest time and Q4 represents the longest time.
  • Figure 5 is a graph showing the association between best response and duration of uSN38>0.03ng/mL for MM-398+5FU/LV arm in NAPOLI-1.
  • Figure 6A is a graph showing the association between unencapsulated SN-38 Cmax and Neutropenia Grade>3 in patients treated with MM-398.
  • Figure 6B is a graph showing the association between total irinotecan Cmax and Diarrhea grade >3 in patients treated with MM-398.
  • Figure 7 A is a graph showing carboxylesterase (CES) activity; increased tumor SN-38 levels were associated with increased tumor deposition, as assessed by tumor CPT-11 at 24 h post administration in SCLC mouse xenograft models.
  • CES carboxylesterase
  • Figure 7B is a graph showing carboxylesterase (CES) activity; SCLC PDX tumors have CES activity comparable to other indications in which irinotecan is active.
  • CES carboxylesterase
  • Figure 7C is a graph showing cell sensitivity; Nal-IRI tumor deposition is consistent with range of SN-38 sensitivity in H1048 SCLC cells.
  • Figure 7D is a graph showing cell sensitivity; cytotoxicity of Topol inhibitors increases with exposure.
  • Figure 7E is a chart showing that topotecan administration is severely limited by toxicity, thus limiting sustained inhibition of topol in comparison to Onivyde mediated prolonged SN-38 exposure.
  • Figure 8A shows the anti-tumor activity of MM-398 in the DMS-53 xenograft model of SCLC.
  • Figure 8B shows the anti-tumor activity of MM-398 in the HC1-H1048 xenograft model of SCLC.
  • Figure 8C shows the percent survival of rats in the H841 rat orthotopic xenograft model of SCLC that are treated with control, Onivyde (30 or 50 mg/kg salt), irinotecan (25 mg/kg) or topotecan (4 mg/kg) at days post inoculation.
  • Figures 9A and 9B are graphs showing the tumor metabolite levels in SCLC xenograft models treated with MM-398 and nonliposomal Irinotecan. At 24 hours post- injection, ( Figure 9 A) CPT-11 and ( Figure 9B) active metabolite SN-38 in tumors were significantly higher for mice treated with MM-398 at 16 mg/kg (salt) compared to
  • nonliposomal irinotecan at 30 mg/kg (salt).
  • Figures 10A and 10B are graphs showing that Nal-IRI is superior to all comparator treatment arms in treatment naive SCLC xenograft models:
  • Figure 10B shows the number of complete response (Nal-IRI).
  • NCI-H1048 is a chemo-sensitive model (established from pleural effusion metastases of SCLC). All nal-IRI-treated animals have complete response (CR) after 2-3 doses - but dose response is observed at early time-point. IRI-treated animals progress after initially responding to treatment; while nal-IRI treated animals remain CR to date.
  • Figures 11 A and 1 IB describe a 2L SCLC xenograft model created through treatment with Carboplatin + Etoposide.
  • FIG. 12 is a graph showing that Nal-IRI remains effective in platinum-treated SCLC tumors and is superior to topotecan and irinotecan: 2L SCLC Model: NC1-H1048.
  • platinum-treated SCLC tumors Nal-IRI remains active and is trending towards complete response; IRI treatment is active but after 3rd cycle some tumors are trending regrowth;
  • Topotecan (at 2x clinically relevant dose) seems to be active after 1-2 cycles but progress quickly after 3rd dose; Etoposide + carboplatin is not tolerable by the 5th cycle.
  • Figures 13 A and 13B are graphs showing that Nal-IRI is also superior to topotecan and irinotecan in another SCLC xenograft model (DMS-114):
  • Figure 13A is a graph showing DMS-114 SCLC Mouse Xenograft (s.c);
  • Figure 13B is a chart showing Nal- IRI (Day 74) tumor volume change.
  • Nal-IRI is superior to irinotecan and topotecan at clinically relevant doses.
  • SCLC tumors respond to irinotecan early on but became less responsive after 2-3 cycles.
  • Figures 14A-4C are graphs showing SCLC tumors treated with TOPI inhibitors remain responsive to nal-IRI.
  • Figure 14A. DMS-114: Treatment Naive; Figure 14B. DMS- 114: Topotecan-Treated; Figure 14C. DMS-114: Irinotecan-Treated. DMS114 tumors treated with topotecan are responsive to nal-IRI (16 mg/kg) but not irinotecan (33 mg/kg).
  • Figures 15A-15C are graphs showing that duration of exposure maybe crucial for TOPI inhibitor activity.
  • Figure 15A is DMS-114 SCLC Mouse Xenograft (s.c);
  • Figure 15B is Hypothesized Tumor Exposure;
  • Figure 15C is NC1-H1048 Mouse Xenograft.
  • bolus given on day 1 topotecan has less anti-tumor activity compared to fractionated topotecan (days 1 & 2). This may be indicative that prolonged exposure of TOPI inhibitor above a therapeutic threshold is more beneficial than high C ma x because irinotecan is a pro-drug (CPT-11), the active metabolite SN-38 may also have a longer duration than topotecan.
  • Figures 16A-16D show NC1-H1048 SCLC Mouse Xenograft (s.c.) Figure 16A. Tumor Volume; Figure 16B. Survival; Figure 16C. Body Weight Change; Figure 16D.
  • Figures 17A-7C show NDMC-53 SCLC Mouse Xenograft (s.c.)
  • Figure 17A Tumor Volume
  • Figure 17B Survival
  • Figures 18A and 18B are graphs showing that Nal-IRI increases exposure and sustains delivery of irinotecan and SN-38 (active metabolite) in BxPC-3 mouse xenograft tumors: Figure 18 A. Plasma; Figure 18B. Tumor.
  • Figure 19 is a graph showing that Nal-IRI effectively delivers irinotecan to tumors in preclinical models of SCLC.
  • Figures 20A and 20B are graphs showing SCLC Tumors treated with TOPI inhibitors remain responsive to nal-IRI: Figure 20 A. DMS-114: Topotecan-Treated; Figure 20B. DMS-114: Treatment Naive. DMS l 14 tumors treated with topotecan are responsive to nal-IRI (16 mg/kg) but not irinotecan (33 mg/kg).
  • Figures 21 A and 2 IB are graphs showing that Nal-IRI remains effective in platinum-treated SCLC tumors and is superior to topotecan and irinotecan in a 2L SCLC Model: NC1-H1048.
  • Figure 21 A shows the change in Tumor Volume;
  • Figure 21B is a survival graph.
  • Figures 22A-22D are graphs showing pre-clinical evidence that MM-398 has improved circulation and tumor circulation in a HT29 CRC xenograft model - MM-398 40mg/kg: Figure 22A CPT-11 plasma (sustained plasma levels), Figure 22B. SN-38 plasma (moderately sustained plasma levels), Figure 22C CPT-11 tumor (sustained intra-tumor levels), and Figure 22D SN-38 tumor (enhanced intra-tumor activation to SN38).
  • Figures 23A-23F are graphs showing Nal-IRI has greater anti -tumor activity than irinotecan and topotecan.
  • NOD/SCID mice with subcutaneous ( Figure 23 A) DMS-53, ( Figure 23B) DMS-114 or ( Figure 23C) NCI-H1048.
  • SCLC xenograft tumors were treated with IV nal-IRI (16 mg/kg; triangles), IV irinotecan (33 mg/kg; diamonds), IP topotecan (0.83 mg/kg/wk days 1-2; squares) or vehicle control (circles).
  • MM-398 is a liposomal encapsulation of irinotecan that provides sustained tumor exposure of SN-38 and therefore provides certain advantages over nonliposomal irinotecan.
  • the approved regimen of MM-398 in patients with pancreatic cancer is in combination with 5-FU/LV.
  • 5-FU is not an active agent used in the treatment of SCLC.
  • the treatment of patients with SCLC with MM-398 has not been disclosed. Applicants have discovered certain methods and uses of MM-398 monotherapy in patients with SCLC, including the methods and uses disclosed herein.
  • MM-398 for use in patients with SCLC was based in part on preclinical data and clinical pharmacology analysis described herein.
  • the methods and uses are designed to balance increased efficacy with increased toxicity predicted at higher doses.
  • Preclinical data herein indicate the activity of MM-398 in models of SCLC.
  • Clinical pharmacology analysis supports increased toxicity at increased doses and specifically supports the safety profile of the 90 mg/m 2 dose.
  • preclinical efficacy data at mouse dose levels equivalent to 90 mg/m 2 in humans are shown to be superior to topotecan.
  • a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC can be treated with an antineoplastic therapy consisting of a single dose of a therapeutically effective amount of irinotecan encapsulated in liposomes.
  • the liposomal irinotecan can be a pharmaceutically acceptable liposome formulation of irinotecan, comprising irinotecan in a delivery form having a diameter of about 100 nm, such as an liposomal irinotecan (Example 1), including PEGylated liposomes.
  • Various suitable liposomal irinotecan preparations can be
  • the liposomal irinotecan is the product MM-398 (ONIVYDE) (Example 9).
  • 90 mg/m 2 irinotecan refers to the free base, encapsulated in liposomes (dose based on the amount of irinotecan free base) and is equivalent to 100 mg/m 2 of the irinotecan hydrochloride anhydrous salt).
  • Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by multiplying the dose based on irinotecan hydrochloride trihydrate with the ratio of the molecular weight of irinotecan free base (586.68 g/mol) and the molecular weight of irinotecan hydrochloride trihydrate (677.19 g/mol).
  • This ratio is 0.87 which can be used as a conversion factor.
  • an 80 mg/m 2 dose based on irinotecan hydrochloride trihydrate is equivalent to a 69.60 mg/m 2 dose based on irinotecan free base (80 x 0.87). In the clinic this is rounded to 70 mg/m 2 to minimize any potential dosing errors.
  • 50 mg/m 2 based on irinotecan as free base is equivalent to 60 mg/m 2 based on irinotecan as the hydrochloride trihydrate
  • 70 mg/m 2 based on irinotecan as free base is equivalent to 80 mg/m 2 based on irinotecan as the hydrochloride trihydrate
  • 90 mg/m 2 based on irinotecan as free base is equivalent to 100 mg/m 2 based on irinotecan as the hydrochloride trihydrate
  • 100 mg/m 2 based on irinotecan as free base is equivalent to 120 mg/m 2 based on irinotecan as the hydrochloride trihydrate, in accordance with Table 1.
  • Table 2 Total Irinotecan and Total SN-38
  • the C max of SN-38 increases proportionally with liposomal irinotecan dose but the AUC of SN-38 increases less than proportionally with dose, enabling new methods of dosage adjustment.
  • the value of the parameter associated with adverse effects (Cmax) decreases by a relatively greater extent than the value of the parameter associated with the effectiveness of treatment (AUC).
  • AUC effectiveness of treatment
  • a reduction in the dosing of the liposomal irinotecan can be implemented that maximizes the difference between the reduction in Cmax and in AUC.
  • the discovery means that in treatment regimens, a given SN-38 AUC can be achieved with a surprisingly low SN-38 Cmax. Likewise, a given SN-38 Cmax can be achieved with a surprisingly high SN-38 AUC.
  • the liposomal irinotecan can be characterized by the parameters in Table 2.
  • the liposomal irinotecan can be MM-398 or a product that is bioequivalent to MM-398.
  • the liposomal irinotecan can be characterized by the parameters in Table 3, including a Cmax and/or AUC value that is 80-125%) of the corresponding value in Table 2.
  • the pharmacokinetic parameters of total irinotecan for various alternative liposomal irinotecan formulations administering 90 mg/m 2 irinotecan free base once every two weeks is provided in Table 3.
  • an antineoplastic therapy consisting of liposomal irinotecan in a pharmaceutically acceptable injectable form can be administered once every two weeks to patients with SCLC disease that has progressed after having received previous antineoplastic therapy (e.g., prior platinum-based therapies alone or with other chemotherapeutic agents).
  • the dose of liposomal irinotecan e.g., 50-90 mg/m 2 irinotecan (free base) encapsulated in irinotecan liposomes
  • dose frequency e.g., once every 2 weeks
  • the dose can be selected to provide a tolerable patient dose, including a dose providing acceptably low levels of grade 3 or greater neutropenia (Figure 6A) and/or diarrhea (Figure 6B), as described in Example 6.
  • the patient may receive other agents that are not antineoplastic agents, such as anti-emetic agents.
  • the antineoplastic therapy can be administered in the absence of topotecan.
  • the invention is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum- based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 90 mg/m 2 (free base) of irinotecan encapsulated in irinotecan liposomes.
  • SCLC small cell lung cancer
  • the invention is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 70 mg/m 2 (free base) of irinotecan encapsulated in irinotecan liposomes.
  • SCLC small cell lung cancer
  • the invention is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 50 mg/m 2 (free base) of irinotecan encapsulated in irinotecan liposomes.
  • SCLC small cell lung cancer
  • the methods of treatment can include determining whether a patient meets one or more inclusion criteria specified in Example 7, and then administering the antineoplastic therapy consisting of liposomal irinotecan.
  • an antineoplastic therapy can consist of administering a therapeutically effective dose (e.g., 50-90 mg/m 2 irinotecan (free base) encapsulated in liposomes) and dose frequency (e.g., once every 2 weeks) of liposomal irinotecan to a patient who has been treated for SCLC with a platinum-based therapy (e.g., cisplatin and/or carboplatin alone or in combination with etoposide).
  • a therapeutically effective dose e.g., 50-90 mg/m 2 irinotecan (free base) encapsulated in liposomes
  • dose frequency e.g., once every 2 weeks
  • the methods of treatment can include determining whether a patient meets one or more exclusion criteria specified in Example 7, and not administering the antineoplastic therapy consisting of liposomal irinotecan.
  • Methods of treating SCLC disclosed herein can include administering the antineoplastic therapy to a patient who does not meet one or more exclusion criteria in Example 7.
  • an antineoplastic therapy can consist of administering a therapeutically effective dose (e.g., 50-90 mg/m 2 irinotecan (free base) encapsulated in liposomes) and dose frequency (e.g., once every 2 weeks) of liposomal irinotecan to a patient who has not been treated for SCLC with irinotecan or topotecan.
  • a therapeutically effective dose e.g., 50-90 mg/m 2 irinotecan (free base) encapsulated in liposomes
  • dose frequency e.g., once every 2 weeks
  • Certain subgroup of patients diagnosed with SCLC may optionally be treated with a reduced dose of the liposomal irinotecan, including patients who have higher levels of bilirubin or patients with UGT1A1 *28 7/7 homozygous allele.
  • the reduced dose refers to a dose of less than 90 mg/m 2 of irinotecan (free base) encapsulated in liposomes administered once every two weeks to the patient receiving the reduced dose.
  • the reduced dose can be a dose of 50-90 mg/m 2 , including a reduced dose of 50 mg/m 2 , a reduced dose of 60 mg/m 2 , a reduced dose of 70 mg/m 2 or a reduced dose of 80 mg/m 2 irinotecan (free base) administered once every two weeks to patients diagnosed with SCLC and receiving the reduced dose.
  • the first dose reduction should be to 50 mg/m 2 and then to 43 mg/m 2 .
  • the exact determination of the appropriate dose will be dependent on the observed pharmacokinetics, efficacy, and safety in that subpopulation.
  • the liposomal irinotecan can be administered to patients diagnosed with SCLC disease progression on or after immunotherapy and/or after first-line platinum based chemotherapy (carboplatin or cisplatin) or chemo-radiation including platinum-based chemotherapy for treatment of limited or extensive stage SCLC.
  • the patient can receive some form of immunotherapy for SCLC prior to administration of the liposomal irinotecan.
  • immunotherapy can include atezolizumab, avelimumab, nivolumab, pembrolizumab, ipilimumab, tremelimumab and/or durvalumab.
  • a patient receives nivolumab for SCLC (e.g., according to a treatment regimen in NCT02481830) prior to receiving the liposomal irinotecan as disclosed herein.
  • a patient receives ipilimumab for SCLC (e.g., according to a treatment regimen in NCT01331525, NCT02046733, NCT01450761, NCT02538666 or NCT01928394) prior to receiving the liposomal irinotecan as disclosed herein.
  • the immunotherapy can include molecules that bind to CTLA4, PDLl, PDl, 41BB and/or OX40 including the publicly available compounds in the Table 4 below or other compounds that bind to the same epitope or have the same or similar biological functions.
  • the use of a combination of liposomal irinotecan and an immunotherapy can be used for the treatment of cancer in a host in need thereof, in an amount and in a schedule of administration that is therapeutically synergistic in the treatment of said cancer.
  • the immunotherapy can be an antibody or combination of antibodies binding to and/or acting upon alpha-PDLl, alpha-41BB, alpha-CTLA4, alpha-OX40 and/or PDl .
  • the treatment of cancer in a host in need thereof comprises the administration of MM-398 without the administration of steroids.
  • the treatment schedule can comprise administering MM-398 once every two or three weeks or two out of three weeks at 43, 50, 70, 80 or 90 mg/m 2 liposomal irinotecan (free base) in combination with an immunotherapy (e.g., in combination with an antibody to alpha-PDLl, PD1, alpha-41BB, alpha-CTLA4 and/or alpha-OX40).
  • the treatment schedule can comprise administering a (e.g., 28-day) treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 43, 50, 70, 80 or 90 mg/m 2 liposomal irinotecan (free base) followed by the administration of 3 mg/kg nivolumab, once every two weeks; and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • a (e.g., 28-day) treatment cycle to a human host diagnosed with SCLC
  • the treatment cycle includes administration of: a total of 43, 50, 70, 80 or 90 mg/m 2 liposomal irinotecan (free base) followed by the administration of 3 mg/kg nivolumab, once every two weeks; and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering a (e.g., 28-day) treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 43, 50, 70, 80 or 90 mg/m 2 liposomal irinotecan (free base) once every two or three weeks or two out of three weeks, followed by the administration of 2 mg/kg pembrolizumab, once every two or three weeks (where the first dose of liposomal irinotecan and pembrolizumab are given on the same day); and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering MM-398 once every two weeks at 90 mg/m 2 liposomal irinotecan (free base).
  • a method of treating a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC can consist of administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 50, 70 or 90 mg/m 2 (free base) of irinotecan encapsulated in irinotecan liposomes.
  • each dose of irinotecan liposome can be reduced (e.g., 50, or 70 mg/m 2 ).
  • each dose of irinotecan liposome can be 90 mg/m 2 .
  • the method can further comprise administering a corticosteroid and an anti-emetic to the patient prior to the administration of the irinotecan liposome.
  • a method of treating a human patient not homozygous for the UGT1 Al *28 allele and diagnosed with small cell lung cancer (SCLC) after disease progression following prior therapy for the SCLC can comprise administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 90 mg/m 2 of irinotecan (free base) encapsulated in a irinotecan liposomes.
  • the method can further comprise administering a corticosteroid and an anti-emetic to the patient prior to the administration of the irinotecan liposome.
  • the patient Prior to receiving the antineoplastic therapy of liposomal irinotecan, the patient can be a patient who has progressed on a platinum-based regimen and who has also
  • the patient can be a patient who was not treated with topotecan for the SCLC prior to receiving the liposomal irinotecan antineoplastic therapy.
  • the patient can previously receive immunotherapy induction, followed and/or accompanied by one or more maintenance doses of chemotherapy, prior to administration of the liposomal irinotecan.
  • the treatment schedule can comprise administering MM-398 once every three weeks at 100-130 mg/m 2 liposomal irinotecan (free base) in combination with an
  • the treatment schedule can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) followed by the administration of 3 mg/kg nivolumab, once every three weeks; and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) once every three weeks combined with the administration of 3 mg/kg nivolumab, once every two or three weeks (where the first dose of liposomal irinotecan and nivolumab are given on the same day); and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) once every three weeks combined with the administration of 3 mg/kg nivolumab, once every two or three weeks (where the first dose of liposomal irinotecan and nivolumab are given on the same day); and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) followed by the administration of 2 mg/kg pembrolizumab, once every three weeks; and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) once every three weeks combined with the administration of 2 mg/kg pembrolizumab, once every two or three weeks (where the first dose of liposomal irinotecan and pembrolizumab are given on the same day); and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) once every two out of three weeks combined with the administration of 2 mg/kg pembrolizumab, once every two or three weeks (where the first dose of liposomal irinotecan and pembrolizumab are given on the same day); and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment cycle includes administration of: a total of 100, 110, 120, or 130 mg/m 2 liposomal irinotecan (free base) once every two out of three weeks combined with the administration of 2 mg/kg pembrolizumab, once every two or three weeks (where the first dose of liposomal irinotecan and pembrolizumab are given on the same day); and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the treatment schedule can comprise administering MM-398 once every three weeks at 110 mg/m 2 liposomal irinotecan (free base), in combination with a therapeutically effective amount of an immunotherapy (e.g., in combination with an antibody to alpha-PDLl, PD1, alpha-41BB, alpha-CTLA4 and/or alpha-OX40).
  • the treatment schedule can comprise administering MM-398 once every three weeks at 100 mg/m 2 liposomal irinotecan (free base), in combination with a therapeutically effective amount of an immunotherapy (e.g., in combination with an antibody to alpha-PDLl, PD1, alpha-41BB, alpha-CTLA4 and/or alpha- OX40).
  • the treatment schedule can comprise administering MM-398 once every three weeks at 120 mg/m 2 liposomal irinotecan (free base) , in combination with a therapeutically effective amount of an immunotherapy (e.g., in combination with an antibody to alpha-PDLl, PD1, alpha-41BB, alpha-CTLA4 and/or alpha-OX40).
  • the treatment schedule can comprise administering MM-398 once every three weeks at 130 mg/m 2 liposomal irinotecan (free base) , in combination with a therapeutically effective amount of an immunotherapy (e.g., in combination with an antibody to alpha-PDLl, PD1, alpha-41BB, alpha-CTLA4 and/or alpha- OX40).
  • liposomal irinotecan is administered after disease progression following platinum-based therapy for the SCLC in combination with one or more of prexasertib, aldoxombicin, lurbinectedin and Rova-T.
  • the liposomal irinotecan can be administered to a patient who has previously received a PD-1 directed therapeutic (e.g., nivolumab, pembrolizumab), a PD-Ll directed therapeutic (e.g.,
  • the liposomal irinotecan can be administered in combination with a Chkl directed therapeutic (e.g., prexasertib), a Topo-2 directed therapeutic (e.g., aldozurubicin), a DNA inhibitor (e.g., lurbinectedin) or a Notch ADC compound (e.g., Rova-T).
  • a Chkl directed therapeutic e.g., prexasertib
  • a Topo-2 directed therapeutic e.g., aldozurubicin
  • a DNA inhibitor e.g., lurbinectedin
  • a Notch ADC compound e.g., Rova-T
  • the liposomal irinotecan can be administered in combination with a Chkl directed therapeutic (e.g., prexasertib), a Topo-2 directed therapeutic (e.g., aldozurubicin), a DNA inhibitor (e.g., lurbin
  • the liposomal irinotecan can be administered to a patient who has previously received cisplatin or carboplatin for SCLC, and the liposomal irinotecan is administered in the absence of (i.e., without) cisplatin or carboplatin (for second or subsequent lines of therapy).
  • a Chkl directed therapeutic e.g., prexasertib
  • a Topo-2 directed therapeutic e.g., aldozurubicin
  • a DNA inhibitor e.g., lurbinectedin
  • a Notch ADC compound e.g., Rova-T
  • the liposomal irinotecan can be administered to a patient who has previously received cisplatin or carboplatin for SCLC, and the liposomal irinotecan is administered in the absence of (i.e., without) cisplatin or carboplatin (for second or subsequent lines of therapy).
  • methods of treating SCLC can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 90 mg/m 2 liposomal irinotecan (free base) or 120
  • the treatment schedule can comprise administering a treatment cycle to a human host diagnosed with SCLC, where the treatment cycle includes administration of: a total of 90 mg/m 2 liposomal irinotecan (free base) or 120 mg/m 2 liposomal irinotecan (free base) once every three weeks combined with the administration of 2 mg/kg pembrolizumab once every three weeks starting on the same day as the first administration of the liposomal irinotecan; and repeating said treatment cycle until a progression or an unacceptable toxicity is observed.
  • the patient can be administered antineoplastic therapy for treatment of SCLC comprising 90 mg/m 2 liposomal irinotecan once every two weeks, without the administration of another antineoplastic agent (e.g., without the administration of topotecan).
  • the antineoplastic therapy for previously treated (e.g. second line) SCLC provides a median time to progression of progression free survival of greater than 15 weeks (e.g., at least about 20-25 weeks, including about 21-24 weeks, about 22-24 weeks, about 23 weeks or about 24 weeks), a median overall survival of greater than 30 weeks (e.g., at least about 30-50 weeks, including about 40-50 weeks, about 44-48 weeks, about 45-47 weeks, about 46 weeks or about 47 weeks), with a hazard ratio of less than 1, and preferably less than 0.7, 0.6 or 0.5 (e.g., including hazard ratio of about 0.6-0.7).
  • the antineoplastic therapy provides a major adverse event (grade 3+) occurring in >5% of the population of less than 50% for neutropenia (e.g., about 10-50%, including about 20%), less than 50% for thrombocytopenia (e.g., less than 10%, including 1-10%, 1-5%, less than 5%, and about 2%, about 3% and about 4%), and less than 30% for anemia (e.g., less than 10%, including 1-10%, 1-8%, less than 8%, and about 5-7%, about 6% and about 5%).
  • a major adverse event grade 3+
  • the population of less than 50% for neutropenia (e.g., about 10-50%, including about 20%), less than 50% for thrombocytopenia (e.g., less than 10%, including 1-10%, 1-5%, less than 5%, and about 2%, about 3% and about 4%), and less than 30% for anemia (e.g., less than 10%, including 1-10%, 1-8%, less than 8%, and about 5-
  • a method of treating a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC can consist of administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 90 mg/m 2 (free base) of irinotecan encapsulated in irinotecan liposomes (or reduced doses of 50-70 g/m 2 (free base) of irinotecan as the liposomal irinotecan to patients who have experienced adverse events during or after a prior administration of liposomal irinotecan and/or patients known to be homozygous for the UGT1A1 *28 allele), where the antineoplastic therapy in a clinical trial of at least 300 patients (e.g., about 400-450 patients), where the antineoplastic therapy in a clinical trial of at least 300 patients (e.g., about 400-450 patients) results
  • a method of treating a human patient diagnosed with small cell lung cancer (SCLC) after disease progression following platinum-based therapy for the SCLC can consist of administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a single dose of liposomal irinotecan providing 90 mg/m 2 (free base) of irinotecan encapsulated in irinotecan liposomes (or reduced doses of 50-70 g/m 2 (free base) of irinotecan as the liposomal irinotecan to patients who have experienced adverse events during or after a prior administration of liposomal irinotecan and/or patients known to be homozygous for the UGT1A1 *28 allele), where the antineoplastic therapy in a clinical trial of at least 300 patients (e.g., about 400-450 patients) results in one or more of the following: median time to progression of progression free survival of greater than 15 weeks (e.g., at least
  • each dose of irinotecan liposome can be reduced (e.g., 50, or 70 mg/m 2 ).
  • each dose of irinotecan liposome can be 90 mg/m 2 .
  • the method can further comprise administering a corticosteroid and an anti-emetic to the patient prior to the administration of the irinotecan liposome.
  • the liposomal irinotecan can be administered to patients diagnosed with small cell lung cancer (SCLC) disease progression following treatment with one or more camptothecin compounds or topoisomerase I (Topo-1) inhibitors.
  • SCLC small cell lung cancer
  • camptothecin compounds or topoisomerase I (Topo-1) inhibitors include, but are not limited to, camptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, 10-hydroxycamptothecin, 7- ethyl 10-hydroxy camptothecin , 9-nitrocamptothecin, 10, 11 -methyl enedioxycamptothecin, 9-amino-10,l 1 -methyl enedioxycamptothecin, 9-chloro-10, l 1 -methyl enedioxycamptothecin, innotecan (CPT-11), topotecan, lurtotecan, silatecan, etirinotecan pegol, rubitecan, exatecan, FL118, belotecan, gimatecan, indotecan, indimitecan, (7-(4-methylpiperazinomethylene)- 10, 11 -ethyl enedioxy-20(S)-camptothecin,
  • the liposomal innotecan can be administered to patients diagnosed with SCLC disease progression following treatment with innotecan (CPT-11), topotecan, or both.
  • the liposomal irinotecan can be administered to patients diagnosed with SCLC disease progression following treatment with irinotecan (CPT- 11).
  • the liposomal irinotecan can be administered to patients diagnosed with SCLC disease progression following treatment with topotecan.
  • the liposomal irinotecan can be administered to patients diagnosed with SCLC disease progression following treatment with non-liposomal irinotecan.
  • the platinum-based therapy is administered in combination with etoposide or non-liposomal irinotecan. In some embodiments, the platinum-based therapy is administered in combination with etoposide. In some embodiments, the platinum- based therapy is administered in combination with non-liposomal irinotecan.
  • One embodiment is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after camptothecin-based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a 90 mg/m 2 (free base) dose of MM-398 liposomal irinotecan.
  • the camptothecin-based therapy comprises the prior, discontinued administration of topotecan or non-liposomal irinotecan to treat the human patient diagnosed with SCLC.
  • the camptothecin-based therapy comprises the prior, discontinued administration of non-liposomal irinotecan administered to the human patient at a 300 mg/m 2 dose once every three weeks. In some embodiments, the camptothecin-based therapy comprises the prior, discontinued
  • the human patient diagnosed with SCLC is platinum sensitive. In some embodiments the human patient diagnosed with SCLC is platinum resistant.
  • a first aspect of the present disclosure is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after first- line platinum-based therapy for the SCLC.
  • One embodiment of the first aspect is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after first-line platinum-based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a 90 mg/m2 (free base) dose of MM-398 liposomal irinotecan.
  • the platinum-based therapy comprises the prior, discontinued administration of cisplatin or carboplatin to treat the human patient diagnosed with SCLC.
  • the human patient has a blood ANC greater than 1,500 cells/microliter without the use of hematopoietic growth factors, prior to the administration of the MM-398 liposomal irinotecan.
  • Another embodiment is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after first-line platinum-based therapy for the SCLC.
  • SCLC small cell lung cancer
  • Yet another embodiment is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after first-line platinum-based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of a 90 mg/m2 (free base) dose of MM-398 liposomal irinotecan wherein the human patient has a blood platelet count of greater than 100,000 cells per microliter, prior to the administration of the MM-398 liposomal irinotecan.
  • SCLC small cell lung cancer
  • the human patient has a blood
  • the human patient has a serum creatinine of less than or equal to 1.5xULN and a creatinine clearance of greater than or equal to 40 mL/min prior to the administration of the MM-398 liposomal irinotecan.
  • the human patient has not received a topoisomerase I inhibitor prior to administration of the MM-398 liposomal irinotecan. In yet other embodiments of the first aspect the human patient has not received more than a single platinum-based therapy prior to administration of the MM-398 liposomal irinotecan.
  • Embodiments of the first aspect may comprise a method wherein the antineoplastic therapy comprises the steps of: (a) preparing a pharmaceutically acceptable injectable composition by combining dispersion of MM-398 liposomal irinotecan containing 4.3 mg irinotecan free base/mL of the dispersion with a 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection to obtain the injectable composition having a final volume of 500 mL and 90 mg/m 2 (free base) of the MM-398 liposomal irinotecan ( ⁇ 5%); and (b) administering the injectable composition from step (a) containing the MM-398 irinotecan liposome to the patient in a 90-minute infusion.
  • D5W Dextrose Injection
  • Sodium Chloride Injection 0.9% Sodium Chloride Injection
  • the method may further comprise administering to the human patient dexamethasone and a 5-HT3 blocker prior to each administration of the antineoplastic therapy, and optionally further administering an antiemetic to the human patient.
  • a second aspect of the present disclosure is a method of treating a human patient who is not homozygous for the UTG1A1 *28 allele and is diagnosed with small cell lung cancer (SCLC) following disease progression on or after first-line platinum-based therapy for the SCLC.
  • SCLC small cell lung cancer
  • One embodiment of the second aspect is a method of treating a human patient who is not homozygous for the UTG1A1 *28 allele and is diagnosed with small cell lung cancer (SCLC) following disease progression on or after first-line platinum-based therapy for the SCLC, the method comprising administering to the human patient an antineoplastic therapy once every two weeks in a six-week cycle, the antineoplastic therapy consisting of a 90 mg/m2 (free base) dose of MM-398 liposomal irinotecan.
  • SCLC small cell lung cancer
  • the platinum-based therapy comprises the prior, discontinued administration of cisplatin or carboplatin to treat the human patient diagnosed with SCLC.
  • One embodiment of the second aspect is a method of treating a human patient who is not homozygous for the UTG1A1 *28 allele and is diagnosed with small cell lung cancer (SCLC) following disease progression on or after first-line platinum-based therapy for the SCLC, wherein the method comprises administering to the human patient an antineoplastic therapy once every two weeks in a six-week cycle, the antineoplastic therapy consisting of a 90 mg/m2 (free base) dose of MM-398 liposomal irinotecan, wherein the human patient has one or more of the following prior to the administration of the MM-398 liposomal irinotecan: (a) a blood ANC greater than 1,500 cells/microliter without the use of hematopoietic growth factors; (b) a blood platelet count of greater than 100,000 cells per microliter; (c) a blood hemoglobin greater than 9 g/dL; and (d) a serum creatinine of less than or equal to 1.5xULN and
  • SCLC
  • the human patient has not received a topoisomerase I inhibitor prior to administration of the MM-398 liposomal irinotecan; and the human patient has not received a more than a single platinum-based therapy prior to administration of the MM-398 liposomal irinotecan.
  • the method comprises administering the antineoplastic therapy for at least three six-week cycles.
  • the antineoplastic therapy comprises the steps of: (a) preparing a pharmaceutically acceptable injectable composition by combining dispersion of MM-398 liposomal irinotecan containing 4.3 mg irinotecan free base/mL of the dispersion with a 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection to obtain the injectable composition having a final volume of 500 mL and 90 mg/m2 (free base) of the MM-398 liposomal irinotecan ( ⁇ 5%); and (b) administering the injectable composition from step (a) containing the MM-398 irinotecan liposome to the patient in a 90-minute infusion.
  • This embodiment may further comprise administering to the human patient dexamethasone and a 5-HT3 blocker prior to each administration of the antineoplastic therapy, and optionally further administering an antiemetic to the human patient.
  • a third aspect of the disclosure provides methods of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after a first-line platinum-based therapy for the SCLC selected from the group consisting of cisplatin or carboplatin.
  • SCLC small cell lung cancer
  • One embodiment of the third aspect is a method of treating a human patient diagnosed with small cell lung cancer (SCLC) following disease progression on or after a first-line platinum-based therapy for the SCLC selected from the group consisting of cisplatin or carboplatin.
  • the method comprising administering to the human patient an antineoplastic therapy once every two weeks for a total of at least three six-week cycles, the antineoplastic therapy consisting of a 90 mg/m2 (free base) dose of MM-398 liposomal irinotecan; wherein the human patient is not homozygous for the UTG1A1 *28 allele and has the following prior to the administration of each antineoplastic therapy of MM-398 liposomal irinotecan: (a) a blood ANC greater than 1,500 cells/microliter without the use of hematopoietic growth factors; (b) a blood platelet count of greater than 100,000 cells per microliter; (c) a blood hemoglobin greater than 9 g/dL; and (d) a serum creatinine of less than or equal to 1.5xULN and a creatinine clearance of greater than or equal to 40 mL/min.
  • antineoplastic therapy consisting of a 90 mg/m2 (free base) dose of MM
  • the human patient has not received a topoisomerase I inhibitor prior to administration of the MM-398 liposomal irinotecan and has not received a more than a single platinum-based therapy prior to administration of the MM-398 liposomal irinotecan; and the method further comprises administering to the human patient dexamethasone and a 5-HT3 blocker prior to each administration of the antineoplastic therapy, and optionally further administering an antiemetic to the human patient.
  • the antineoplastic therapy comprises the steps of: (a) preparing a pharmaceutically acceptable injectable composition by combining dispersion of MM-398 liposomal irinotecan containing 4.3 mg irinotecan free base/mL of the dispersion with a 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection to obtain the injectable composition having a final volume of 500 mL and 90 mg/m2 (free base) of the MM-398 liposomal irinotecan ( ⁇ 5%); and (b) administering the injectable composition from step (a) containing the MM-398 irinotecan liposome to the patient in a 90-minute infusion.
  • D5W Dextrose Injection
  • Sodium Chloride Injection 0.9% Sodium Chloride Injection
  • Example 1 Liposomal Irinotecan
  • the liposomal irinotecan composition preferably comprises or consists of phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl- ethanolamine.
  • the liposomal irinotecan can include unilamellar lipid bilayer vesicles comprising the phosphatidylcholine and cholesterol, encapsulating irinotecan sucrose octasulfate.
  • the irinotecan liposomes in the liposomal irinotecan composition have a diameter of 110 nm ( ⁇ 20%).
  • the liposomal irinotecan can comprise irinotecan sucrose octasulfate encapsulated in liposomes having a unilamellar lipid bilayer vesicle,
  • the vesicle is composed of l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) (e.g., about 6.8 mg/mL), cholesterol (e.g., about 2.2 mg/mL), and methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) (e.g., about 0.1 mg/mL).
  • DSPC l,2-distearoyl-sn-glycero-3-phosphocholine
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • Each mL also contains 2-[4-(2-hydroxyethyl) piperazin-l-yl]ethanesulfonic acid (HEPES) as a buffer (e.g., about 4.1 mg/mL) and sodium chloride as an isotonicity reagent (e.g., about 8.4 mg/mL).
  • HEPES 2-[4-(2-hydroxyethyl) piperazin-l-yl]ethanesulfonic acid
  • sodium chloride as an isotonicity reagent
  • the lipid membrane of the liposomal irinotecan can be composed of
  • ONIVYDE® (also referred to herein as MM-398 or nal-IRI) is a preferred liposomal irinotecan, comprising small unilamellar lipid bilayer vesicle (SUV), approximately 110 nm in diameter that encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state as the sucrosofate salt.
  • SUV small unilamellar lipid bilayer vesicle
  • the ONIVYDE liposomal irinotecan comprises irinotecan sucrose octasulfate encapsulated in liposomes having a unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, which encapsulates an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt; wherein the vesicle is composed of l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) (6.8 mg/mL), cholesterol (2.2 mg/mL), and methoxy-terminated polyethylene glycol (MW 2000)- distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) (0.1 mg/mL).
  • DSPC l,2-distearoyl-sn-glycero-3-phosphocholine
  • MPEG-2000-DSPE methoxy-terminated poly
  • Each mL also contains 2-[4-(2-hydroxy ethyl) piperazin-l-yl]ethanesulfonic acid (HEPES) as a buffer (4.1 mg/mL) and sodium chloride as an isotonicity reagent (8.4 mg/mL).
  • HEPES 2-[4-(2-hydroxy ethyl) piperazin-l-yl]ethanesulfonic acid
  • ONIVYDE is a sterile, white to slightly yellow opaque isotonic liposomal dispersion.
  • the liposomal irinotecan can be supplied as a sterile, white to slightly yellow, opaque liposomal dispersion in a 10 mL single use glass vial, containing 43 mg/10 mL irinotecan free base.
  • the liposomal dispersion in the vial can be diluted prior to intravenous infusion over 90 minutes.
  • the present disclosure provides for use of liposomal irinotecan (e.g., ONIVYDE described in Example 9) for the treatment of SCLC once every two weeks at a total dose of 90 mg/m 2 irinotecan (free base), encapsulated in liposomes (dose based on the amount of irinotecan free base; equivalent to 100 mg/m 2 of the irinotecan hydrochloride anhydrous salt) IV over 90 minutes, every 2 weeks (preferably, in a 6-week cycle).
  • the recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1 *28 allele is 50 mg/m 2 (free base) administered by intravenous infusion over 90 minutes.
  • the dose of ONIVYDE may be increased to 70 mg/m 2 as tolerated in subsequent cycles. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal.
  • Topoisomerase I inhibition has potent effects on a wide range of cancer cell lines.
  • Reference data in the Wellcome Trust Sanger Institute database of the "Genomics of Drug Sensitivity in Cancer” project are available for 663 cancer cell lines screened for sensitivity to SN-38 (URL www.cancerrxgene.org/translation/Drug/1003).
  • An analysis of this data indicated that SCLC cell lines have similar sensitivity to SN-38 as pancreatic and
  • gastrointestinal cancer cell lines ( Figure 1).
  • cancer cell lines of gastrointestinal (HT-29, HCT-116, LoVo, MKN45) or pancreatic (AsPC-1, BxPC3, CFPAC- 1, MiaPaCa-2) origin for which significant in vivo anti-tumor efficacies of MM-398 have been observed are highlighted by filled circles.
  • SCLC cell lines DMS114 and NCI-H1048 (see below) are also shown as filled circles.
  • mice were inoculated subcutaneously in NCR nu/nu mice. When tumors reached -300 mm 3 in volume, mice were treated with 10 or 20 mg/kg of MM-398 irinotecan hydrochloride, administered intravenously on a weekly basis for 4 weeks. Dose levels were selected to correspond to what is believed to be the clinically relevant mouse dose, based on PK modeling and comparison with clinical PK data. As shown in Figure 3, anti-tumor activity was seen at all dose levels tested in the DMS114 model. Animals with tumors receiving 10 or 20 mg/kg showed tumor regression that was sustained for approximately 20- 27 days past the last dose of MM-398 (2/5 and 4/5 complete regressions at 10 and 20 mg/kg dose, respectively).
  • Example 6 Prediction of safety for a dose of 90 mg/m 2
  • Example 7 A Randomized, Open Label Phase 3 Study of nal-IRI (ONIVYDE® or MM-398) in Patients with Small Cell Lung Cancer Who have Progressed On or After Platinum-based First-Line Therapy
  • Part la The objectives of Part la are to: 1) describe the safety and tolerability of irinotecan liposome injection monotherapy administered every 2 weeks and 2) to determine the irinotecan liposome injection monotherapy dose (90 mg/m 2 or 70 mg/m 2 administered every two weeks) for the Part lb and Part 2 of this study.
  • the objectives of Part lb are to describe the 1) progression free survival rate at 12 weeks, 2) objective response rate (ORR), 3) progression free survival (PFS), 4) overall survival (OS), and 5) safety profile.
  • the primary objective of Part 2 is to compare overall survival following treatment with irinotecan liposome injection with overall survival following treatment with IV topotecan.
  • the secondary objectives of Part 2 are to compare the following between the treatment arms: 1) progression free survival (PFS), 2) objective response rate (ORR), 3) proportion of patients with symptom improvement in cough, in dyspnea and in fatigue as measured by the European Organization for Research and Treatment of Cancer Quality of
  • Exploratory Objectives include: 1) To describe QTcF following treatment with irinotecan liposome injection (Part 1 only), 2) To explore the biomarkers associated with efficacy and safety following treatment with irinotecan liposome injection, 3) To describe the association between UGT1A1 genotype, SN-38 concentration (irinotecan liposome injection treated patients only) and safety, 4) To evaluate the
  • Both Part 1 and Part 2 will consist of three phases: a screening phase, a
  • the Treatment/ Active follow-up phase is the period for the first dose of the study drug through the decision to permanently discontinue study drug treatment.
  • the Long Term follow-up phase is a monthly follow-up for overall survival.
  • the initial number of patients to be enrolled in the Part la safety run-in is 6 patients evaluable for safety.
  • This initial cohort of patients will be treated with irinotecan liposome injection 70 mg/m 2 every 2 weeks.
  • Dose limiting toxicities (DLTs) will be evaluated during the first 28 days of treatment (or 14 days after the 2nd dose of study treatment if there is a treatment delay) to determine if the dose is tolerable. If 2 or more patients receiving irinotecan liposome injection 70 mg/m 2 every 2 weeks have DLTs then the dose will be declared not tolerable. In all other cases an additional cohort of 6 patients treated with irinotecan liposome injection starting at 90 mg/m 2 will be enrolled.
  • the 90 mg/m 2 cohort will only be enrolled if the overall experience in the initial 6 patients treated in the 70 mg/m 2 cohort is judged to be safe enough to reasonably expect that the 90 mg/m 2 dose will be tolerable in the assessment of the Part 1 investigators and the Sponsor. Evaluation of DLTs will follow the same guidelines as the first cohort. If 2 or more patients have DLTs at the 90 mg/m 2 dose then that dose will be considered to exceed the optimal safety and tolerability criteria, and 70 mg/m 2 will be designated as the dose for Part lb and Part lb will initiate administering 70 mg/m 2 of irinotecan liposome injection. If there is 0 or 1 DLT within the safety evaluation period with the 90 mg/m 2 dose, then the decision of which dose to use for Part lb will be made by Part 1 investigators and the Sponsor based on the entire safety experience of both cohorts.
  • Part lb of the study will be initiated.
  • approximately 50 eligible patients will be randomized in a 1 : 1 ratio between the experimental arm (Arm la: 90 mg/m 2 of nal-IRI, every 2 weeks), and the control arm (Arm lb: topotecan 1.5 mg/m2 IV for 5 days, every 21 days).
  • Patients will be randomized to the treatment arms using an Interactive Web Response System (IWRS) at a central location.
  • IWRS Interactive Web Response System
  • randomization in Part lb will use a
  • Platinum resistant patients are defined as patients with disease that either progressed during first-line platinum containing therapy or within 90 days of its completion.
  • Platinum sensitive patients are defined as patients with disease that progressed after 90 days of completion of first line platinum containing therapy.
  • PFS based on investigator assessment
  • PFS based on investigator assessment
  • rate at 12 weeks for irinotecan liposome injection is less than 50%
  • PFS based on investigator assessment
  • rate at 12 weeks for IV topotecan exceeds that of irinotecan liposome injection by at least 5 percentage points
  • Randomization will be stratified, based on the following factors:
  • Tumor responses will be measured and recorded, every 6 weeks (+/- 1 week) by using the RECIST guidelines (version 1.1).
  • the tumor assessment at baseline is CT with contrast (chest/abdomen required and pelvis if clinically indicated) and brain MRI with contrast (CT of brain is acceptable).
  • CT computed tomography
  • brain MRI with contrast
  • Each follow-up tumor assessment should use the same assessment as performed at baseline, unless medically contraindicated. All patients will have imaging of the brain at baseline and at each assessment. Patients who discontinue study treatment, for reasons other than objective disease progression, should continue to be followed-up until radiological documentation of progressive disease.
  • the Sponsor will collect and store all tumor measurement images on all patients throughout the study; however, local radiologist and/or PI assessment will determine disease progression. A review of the scans may be performed by the Sponsor for an independent analysis, including analysis of PFS and/or ORR. All patients will be followed at least monthly until death or study closure, whichever occurs first.
  • a quality of life assessment will be performed using the EORTC-QLQ-C30, EORTC-QLQ-LC13, and the EuroQoL five-dimension, five level health status questionnaire (EQ-5D-5L) in Part lb and Part 2 only. Both instruments will be administered before randomization and prior to dosing at 6 week intervals following start of treatment and at treatment discontinuation and at the 30-day follow-up visit.
  • the primary analysis is planned when at least 333 OS events have occurred.
  • An interim analysis for futility is planned to occur at 30% information time, after at least 100 OS events have occurred.
  • an interim analysis will be conducted when at least 210 OS events (63% information time, at 50% of anticipated death events) have occurred to assess the potential for early stopping due to efficacy of the experimental treatment regimen.
  • a regular review of safety data will be conducted for Part 2 by an independent Data Monitoring Committee (DMC).
  • the DMC will consist of oncology and statistical experts independent of the Sponsor.
  • the first safety review of the DMC will take place in Part 2 after the 30th patient is treated for at least one cycle or after the 30th patient discontinued study drug, whichever occurs first.
  • Plasma samples for PK will be collected in Cycle 1 only at the following time points:
  • Part la, and Part lb, Arm la (nal-IRI arm; cycle 1 only):
  • Part 2, Arm 2a (irinotecan liposome injection arm; cycle 1 only):
  • - Day 8 Cycle 1 Day 8 (+/- 1 day), at any time of day.
  • AST Aspartate aminotransferase
  • ALT alanine aminotransferase
  • More than one line of immunotherapy e.g. nivolumab, pembrolizumab, ipilimumab, atezolizumab, tremelimumab and/or durvalumab.
  • One line of immunotherapy is defined as the following: monotherapy or combination of immunotherapy agents given as either (i) in combination with chemotherapy followed by immunotherapy maintenance in the first line setting, (ii) only as a maintenance following response to first-line chemotherapy or
  • Severe arterial thromboembolic events e.g. myocardial infarction, unstable angina pectoris, stroke
  • NYHA Class III or IV congestive heart failure e.g. acute bacterial infection, tuberculosis, active hepatitis B or active HIV
  • Active infection e.g. acute bacterial infection, tuberculosis, active hepatitis B or active HIV
  • Known hypersensitivity to any of the components of irinotecan liposome injection, other liposomal products, or topotecan Known hypersensitivity to any of the components of irinotecan liposome injection, other liposomal products, or topotecan
  • Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1.
  • Part lb will be initiated following dose selection in Part la.
  • Arm la experimental arm: irinotecan liposome injection
  • Randomization must occur within 7 days of planned dosing.
  • Part 2 [0195] Part 2 will be initiated upon passing the stopping criteria and based on the decision of the Sponsor in consultation with the academic steering committee.
  • IWRS interactive web response system
  • Arm 2a (experimental arm): irinotecan liposome injection
  • Arm 2b (control arm): IV topotecan
  • Randomization must occur within 7 days of planned dosing. The randomization will be stratified based on the following prognostic factors:
  • Platinum resistant patients are defined as patients with disease that either progressed during first-line platinum containing therapy or within 90 days of its completion.
  • Platinum sensitive patients are defined as patients with disease that progressed after 90 days of completion of first line platinum containing therapy.
  • Irinotecan liposome injection will be administered at a dose of 70 mg/m2 (strength expressed based on irinotecan free base; approximately equivalent to 80 mg/m2 of the anhydrous salt) IV over 90 minutes, every 2 weeks in a 6-week cycle. Should the 70 mg/m2 dose be deemed tolerable and 90 mg/m2 is explored, irinotecan liposome injection should be administered at 90 mg/m2 (strength expressed based on irinotecan free base; approximately equivalent to 100 mg/m2 of the anhydrous salt) IV over 90 minutes, every 2 weeks in a 6- week cycle.
  • Irinotecan liposome injection will be administered at a dose of 90 mg/m2 (strength expressed based on irinotecan free base; approximately equivalent to 100 mg/m2 of the anhydrous salt): IV over 90 minutes, every 2 weeks in a 6-week cycle (unless deemed unacceptable in Part 1).
  • the appropriate dose of irinotecan liposome injection must be diluted in 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride Injection to a final volume of 500 mL. Care should be taken not to use any diluents other than D5W or 0.9% sodium chloride.
  • UGT1A1 *28 genotype will be collected on all patients and assessed centrally. Results will be provided to the site and to the Sponsor. Sites will also be asked to include the result from the UGT1 Al *28 genotyping on the SAE reporting form.
  • Irinotecan liposome injection 90 mg/m 2 (strength expressed as irinotecan free base; approximately equivalent to 100 mg/m 2 of the anhydrous salt): IV over 90 minutes, every 2 weeks in a 6 week cycle (unless deemed unacceptable in Part 1).
  • the intended dose for topotecan is 1.5 mg/m2 IV for 5 consecutive days every 3 weeks.
  • the dose, administration and dose reductions should follow the guidance as outlined in the prescribing information for IV topotecan.
  • Irinotecan liposome injection also known as nal-IRI, pegylated liposomal irinotecan hydrochloride trihydrate, MM-398, PEP02, BAX2398 and ONIVYDE®
  • nal-IRI pegylated liposomal irinotecan hydrochloride trihydrate, MM-398, PEP02, BAX2398 and ONIVYDE®
  • Each 10 mL single- dose vial contains 43 mg irinotecan free base at a concentration of 4.3 mg/mL.
  • the liposome is a unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, which encapsulates an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt. It will be supplied as sterile, single-use vials containing 43 mg irinotecan free base at a concentration of 4.3 mg/mL. Irinotecan liposome injection must be stored refrigerated (2 to 8°C, 36 to 46°F) with protection from light. Do not freeze.
  • a dose will be decided to be acceptable for proceeding to Part lb if the number of patients with DLTs does not exceed 1 in a cohort of 6 patients. Based on this rule, the probabilities to proceed to Part lb at a dose as a function of true DLT probability rate are shown in Table 6.
  • Part lb The purpose of Part lb is to provide a pilot sample of safety and efficacy data in a randomized setting.
  • the sample size for Part lb was selected for practical purposes to enable curtailment of the study if irinotecan liposome injection is observed to be substantially inferior to topotecan with regard to benefit/risk.
  • An efficacy rule based on the observed PFS rate at 12 weeks, is implemented in this protocol as a formal stopping rule, while additional data will also be considered and may also result in a decision to not proceed to Part 2.
  • a final treatment comparison of PFS will be carried out via a log-rank test when tumor assessments have been completed for all patients in Part lb. If the censoring rate is assumed to be 10%, it is expected that 45 events would have occurred at the time of the final analysis. If the PFS hazard ratio is 0.64 (e.g. irinotecan liposome injection extends median PFS from 3.5 to 5.5 months), then this analysis would have approximate 75% power to detect the treatment difference with a one-sided level 0.20 test.
  • the primary endpoint is overall survival (OS).
  • a total of 420 patients will be randomized in a 1 : 1 ratio to the two treatment arms.
  • Follow-up until at least 333 OS events are observed across the two treatment arms provides at least 85%) power to detect a true hazard ratio of HR ⁇ 0.714 (mOS: 7.5 v 10.5 months) using a stratified log-rank test (stratified by region (North America vs. Asia vs. Other) and platinum sensitivity (sensitive vs. resistant)) with overall 1 -sided significance level of 0.025 (adjusted for interim analyses).
  • Categorical variables will be summarized by frequency distributions (number and percentages of patients) and continuous variables will be summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum).
  • Part 1 Patients enrolled and treated with study drug in Part 1 will comprise the Part 1 safety population. The safety and efficacy of these patients will be presented descriptively.
  • Patients randomized in Part 2 will comprise the intent-to-treat (ITT) population. This will be the population that is evaluated in comparison to evaluate the efficacy of the experimental arm. In the ITT analyses of efficacy, each patient will be considered according to the randomized treatment assignment. Patients who received any part of any study drug will define the Part 2 safety population.
  • ITT intent-to-treat
  • stratification factors will be the randomization
  • OS is defined as the number of months from the date of randomization to the date of death. Patients without observed death at the time of the primary analysis will have OS censored according to the last recorded date alive.
  • the primary analysis will be performed using a stratified log-rank test comparing the OS difference between two treatment arms with 1-sided level of significance at 0.025.
  • Stratification factors will include the randomization stratification factors and classification will be according to the randomization.
  • Kaplan-Meier methods will be used to estimate median OS (with 95% confidence intervals) and to display OS time graphically.
  • a stratified Cox proportional hazards model will be used to estimate hazard ratio and its corresponding 95% confidence interval.
  • Sensitivity analyses for OS will be described in the Statistical Analysis Plan (SAP).
  • Key secondary endpoints are PFS, ORR, proportion of patients with symptom improvement in dyspnea, in cough, and in fatigue. [0256] Key secondary endpoints will tested no more than once. If the primary endpoint of OS is statistically significant at the interim, testing of secondary endpoints will be tested at the interim. Otherwise secondary endpoints will be tested at the final OS analysis if OS if found to be statistically significant at that analysis. Hypothesis testing of key secondary endpoints will be conducted in a stage wise hierarchical manner (Glimm, E, et al., Statistics in Medicine 2010 29:219-228).
  • the nominal level for comparison of PFS will depend on whether the test is performed at the interim or at the planned final analysis and will incorporate an a-spending function similar to that used for OS. If OS and PFS are both significant, then ORR and EORTC-QLQ symptoms will be tested at 1-sided 0.025 level (nominal a adjusted based on spending function, as described for PFS) with each p-value adjusted using the Benjamini- Hochberg correction (Benjamini & Hochberg, J. Royal Statistical Soc. B 2005 57, 289-300) for one-sided a level testing of 4 planned comparisons. Adjusted p-values will be reported, using SAS PROC MULTTEST with FDR option or equivalent algorithm. Any parameter which is not statistically significant will be regarded as descriptive and exploratory.
  • Progression-free survival is the time from randomization to the first documented objective disease progression (PD) using RECIST vl . l or death due to any cause, whichever occurs first. Determination of PFS will be per investigator assessment. If neither death nor progression is observed, data will be censored on the date of the last observed tumor assessment date. Patients without a valid tumor response evaluation at randomization will be censored on the date of randomization. Patients starting a new anti-cancer treatment prior to documented PD will be censored at the date of the last observed tumor assessment prior to start of the new treatment. Patients with documented PD or death after an unacceptable long interval (i.e., 2 or more missed or indeterminate scheduled assessments) will be censored at the time of the last observed non-PD tumor assessment date prior to progression or death.
  • the difference in PFS between treatments will be evaluated using a stratified log- rank test.
  • Kaplan-Meier methods will be used to estimate median PFS (with 95% confidence intervals) and to display PFS time graphically.
  • a stratified Cox proportional hazards model will be used to estimate the PFS hazard ratio and its corresponding 95% confidence interval.
  • ORR Objective response rate
  • Symptom improvement is defined as achievement and 6-week maintenance of symptom subscale scores at least 10 percentage points of scale (following transformation to 0-100 scale) below baseline. Response classifications will be tabulated by treatment group and statistical analyses will compare the proportions of responders for a given symptom.
  • the proportion of patients with improvement will be tabulated by treatment group with 95% confidence intervals based on a Normal approximation. The difference in the proportion of patients with symptom improvement will be presented with corresponding 95% confidence intervals. The proportion of patients with improvement in a symptom will be compared between treatment regimens using Cochran-Mantel-Haenszel method, stratified by region and platinum sensitivity.
  • Safety analyses (adverse events and laboratory analyses) will be performed using the safety population, defined as all patients receiving any study drug. Treatment assignment will be according to actual treatment received. Adverse events will be coded using the latest MedDRA dictionary. Severity will be graded according to the NCI CTCAE version 4.03.
  • Treatment-emergent adverse events are defined as any adverse events reported from the date of first study drug exposure to 30 days after the last date of study drug exposure. Frequency and percentages of patients will be summarized for: any grade TEAE, grade 3 or higher TEAE, study-drug related TEAE, serious TEAE, TEAE leading to dose modification, and TEAE leading to study drug discontinuation. Adverse events will be summarized by System Organ Class and preferred term. All adverse event data will be listed by patient.
  • Laboratory data will be summarized according to parameter type. Where applicable, toxicity grading for laboratory safety parameters will be assigned based on NCI CTCAE version 4.03 criteria.
  • QTcF prolongation with irinotecan liposome injection treatment will be evaluated in patients receiving irinotecan liposome injection in Part 1 of this study.
  • the predicted changes in QTcF will be obtained from the exposure-QTcF relationship using mixed-effect modeling.
  • Sensitivity analyses will be conducted by evaluating by time point and categorical analyses.
  • Plasma pharmacokinetics (PK) of total irinotecan, SN-38, and topotecan will be quantified from the concentration samples using nonlinear mixed effect modeling.
  • the initial PK analysis will use the empirical Bayesian estimation, however, additional covariate analyses will be performed to evaluate alternative baseline factors specific to SCLC.
  • the resulting PK estimates will be used to evaluate the association between PK and PD (efficacy and safety endpoints).
  • Topotecan PK will be used to provide additional data to understand the results from Part lb, by comparing the distribution and the association of PK to
  • Topotecan should only be started in patients with a baseline neutrophil count of greater than or equal to l,500/mm3 (1.5xl09/L) and a platelet count greater than or equal to 100,000/mm 3 (100xl0 9 /L).
  • Topotecan should not be administered in subsequent cycles unless the neutrophil count is >1 x 10 9 /1, the platelet count is >100 x 10 9 /1, and the hemoglobin level is >9 g/dl (after transfusion if necessary). Treatment should be delayed to allow sufficient time for recovery and upon recovery, treatment should be administered according to the guidelines in Table 9 below.
  • Dose reduction decisions should be based on worst preceding toxicity. Moving from dose level 0 to dose level 2 is permitted. Prophylactic antibiotics are recommended for patients at high risk of infectious complications.
  • the dose of topotecan in patients should be reduced to 0.75 mg/m2/day for five consecutive days if the creatinine clearance is between 20 and 39 mL/min.
  • Topotecan should be discontinued if a new diagnosis of interstitial lung disease is confirmed.
  • Example 8 Liposomal irinotecan manufacturing
  • the liposomal irinotecans can be prepared in a multi-step process. First, lipids are dissolved in heated ethanol. The lipids can include DSPC, cholesterol and MPEG-2000-
  • the liposomes can encapsulate irinotecan sucrose octasulfate (SOS) encapsulated in a vesicle consisting of DSPC, cholesterol and MPEG-2000-DSPE combined in a 3 :2:0.015 molar ratio.
  • SOS irinotecan sucrose octasulfate
  • the resulting ethanol-lipid solution is dispersed in an aqueous medium containing substituted amine and polyanion under conditions effective to form a properly sized (e.g.
  • the dispersing can be performed, e.g., by mixing the ethanolic lipid solution with the aqueous solution containing a substituted amine and polyanion at the temperature above the lipid transition temperature, e.g., 60-70 °C, and extruding the resulting hydrated lipid suspension
  • multilamellar liposomes under pressure through one or more track-etched, e.g.
  • the substituted amine can be triethylamine (TEA) and the polyanion can be sucrose octasulfate (SOS) combined in a stoichiometric ratio (e.g., TEA8SOS) at a concentration of about 0.4-0.5N.
  • TEA triethylamine
  • SOS sucrose octasulfate
  • All or substantially all non-entrapped TEA or SOS is then removed (e.g., by gel-filtration, dialysis or ultrafiltration) prior to contacting the liposome with irinotecan under conditions effective to allow the irinotecan to enter the liposome in exchange with TEA leaving the liposome.
  • the conditions can include one or more conditions selected from the group consisting of: addition of the osmotic agent (e.g., 5% dextrose) to the liposome external medium to balance the osmolality of the entrapped TEA-SOS solution and/or prevent osmotic rupture of the liposomes during the loading, adjustment and/or selection of the pH (e.g.
  • the loading of irinotecan by exchange with TEA across the liposome preferably continues until all or substantially all of the TEA is removed from the liposome, thereby exhausting its
  • the irinotecan liposome loading process continues until the gram-equivalent ratio of irinotecan to sucrooctasulfate is at least 0.9, at least 0.95, 0.98, 0.99 or 1.0 (or ranges from about 0.9-1.0, 0.95-1.0, 0.98-1.0 or 0.99- 1.0).
  • the irinotecan liposome loading process continues until the TEA is at least 90%, at least 95%, at least 98%, at least 99% or more of the TEA is removed from the liposome interior.
  • the irinotecan can form irinotecan sucrosofate within the liposome, such as irinotecan and sucrose octasulfate in a molar ratio of about 8: 1.
  • any remaining extra- liposomal irinotecan and TEA is removed to obtain the irinotecan liposome using, e.g., gel (size exclusion) chromatography, dialysis, ion exchange, or ultrafiltration methods.
  • the liposome external medium is replaced with injectable, pharmacologically acceptable fluid, e.g., buffered isotonic saline.
  • the liposome composition is sterilized, e.g., by 0.2- micron filtration, dispensed into dose vials, labeled and stored, e.g., upon refrigeration at 2-8 °C, until use.
  • the liposome external medium can be replaced with pharmacologically acceptable fluid at the same time as the remaining extra-liposomal irinotecan and TEA is removed.
  • the extra-liposomal pH of the composition can be adjusted or otherwise selected to provide a desired storage stability property (e.g., to reduce formation of the lyso-PC within the liposome during storage at 4 °C over 180 days), for example by preparing the
  • composition at a pH of about 6.5-8.0, or any suitable pH value there between (including, e.g., 7.0-8.0, and 7.25).
  • Irinotecan liposomes with the extra-liposomal pH values, irinotecan free base concentration (mg/mL) and various concentrations of sucrose octasulfate can be prepared as provided in more detail as described herein.
  • DSPC, cholesterol (Choi), and PEG-DSPE were weighed out in amounts that corresponded to a 3 :2:0.015 molar ratio, respectively (e.g., 1264 mg/412.5 mg/22.44 mg).
  • the lipids were dissolved in chloroform/methanol (4/1 v/v), mixed thoroughly, and divided into 4 aliquots (A-D). Each sample was evaporated to dryness using a rotary evaporator at 60
  • the pH of the extruded liposomes was adjusted with 1 N NaOH to pH 6.5 as necessary.
  • the liposomes were purified by a combination of ion-exchange chromatography and size-exclusion chromatography. First, DowexTM IRA 910 resin was treated with 1 N NaOH, followed by 3 washes with deionized water and then followed by 3 washes of 3 N HCI, and then multiple washes with water. The liposomes were passed through the prepared resin, and the conductivity of the eluted fractions was measured by using a flow-cell conductivity meter (Pharmacia, Upsalla, Sweden). The fractions were deemed acceptable for further purification if the conductivity was less than 15 ⁇ 8/ ⁇ .
  • the liposome eluate was then applied to a Sephadex G-75 (Pharmacia) column equilibrated with deionized water, and the collected liposome fraction was measured for conductivity (typically less than 1 ⁇ 8/ ⁇ ).
  • Cross- membrane isotonicity was achieved by addition of 40% dextrose solution to a final concentration of 5% (w/w) and the buffer (Hepes) added from a stock solution (0.5 M, pH 6.5) to a final concentration of 10 mM.
  • a stock solution of irinotecan was prepared by dissolving irinotecan » HCl tnhydrate powder in deionized water to 15 mg/mL of anhydrous irinotecan-HCl, taking into account water content and levels of impurities obtained from the certificate of analysis of each batch.
  • Drug loading was initiated by adding irinotecan at 500g/mol liposome phospholipid and heating to 60 ⁇ 0.1 °C for 30 min in a hot water bath. The solutions were rapidly cooled upon removal from the water bath by immersing in ice cold water.
  • Extraliposomal drug was removed by size exclusion chromatography, using Sephadex G75 columns equilibrated and eluted with Hepes buffered saline (10 mM Hepes, 145 mM NaCl, pH 6.5). The samples were analyzed for irinotecan by HPLC and phosphate by the method of Bartlett (see Phosphate Determination).
  • the samples were divided into 4 mL aliquots and the pH was adjusted as indicated in the Results using 1 N HCI or 1 N NaOH, sterile filtered under aseptic conditions, and filled into sterile clear glass vials that were sealed under argon with a Teflon® lined threaded cap and placed in a thermostatically controlled refrigerator at 4 °C.
  • an aliquot was removed from each sample and tested for appearance, size, drug/lipid ratio, and drug and lipid chemical stability.
  • the liposome size was determined in the diluted samples by dynamic light scattering using Coulter Nano-Sizer at 90 degree angle, and presented as Mean ⁇ Standard deviation (nm) obtained by the method of cumulants.
  • Example 9 ONIVYDE (MM-398) Liposomal Irinotecan
  • ONIVYDE irinotecan liposome injection
  • ONIVYDE is a topoisomerase inhibitor, formulated with irinotecan hydrochloride trihydrate into a liposomal dispersion, for intravenous use.
  • ONIVYDE indicated for the treatment of metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine- based therapy.
  • ONIVYDE is a storage stabilized liposome having a pH of about 7.25.
  • the ONIVYDE product contains irinotecan sucrosofate encapsulated in a liposome, obtained from an irinotecan hydrochloride trihydrate starting material.
  • the chemical name of irinotecan is (S)-4, l l-diethyl-3,4,12, 14-tetrahydro-4-hydroxy-3, 14-dioxolH- pyrano[3',4' :6,7]-indolizino[l,2-b]quinolin-9-yl-[l,4'bipiperidine]- -carboxylate.
  • the dosage of ONIVYDE can be calculated based on the equivalent amount of irinotecan trihydrate hydrochloride starting material used to prepare the irinotecan liposomes, or based on the amount of irinotecan in the liposome. There are about 866 mg of irinotecan per gram of irinotecan trihydrate hydrochloride. For example, an ONIVYDE dose of 80 mg based on the amount of irinotecan hydrochloride trihydrate starting material actually contains about 0.866x(80mg) of irinotecan free base in the final product (i.e., a dose of 80 mg/m 2 of
  • ONIVYDE based on the weight of irinotecan hydrochloride starting material is equivalent to about 70 mg/m 2 of irinotecan free base in the final product).
  • ONIVYDE is a sterile, white to slightly yellow opaque isotonic liposomal dispersion. Each 10 mL single-dose vial contains 43 mg irinotecan free base at a concentration of 4.3 mg/mL.
  • the liposome is a unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, which encapsulates an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt.
  • the vesicle is composed of l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 6.81 mg/mL, cholesterol 2.22 mg/mL, and methoxy-terminated polyethylene glycol (MW 2000)- distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) 0.12 mg/mL.
  • DSPC l,2-distearoyl-sn-glycero-3-phosphocholine
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol (MW 2000)- distearoylphosphatidyl ethanolamine
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • MPEG-2000-DSPE methoxy-terminated polyethylene
  • ONIVYDE contains 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.
  • an ONIVYDE unit dosage form is a pharmaceutical composition comprising an amount of irinotecan encapsulated liposomes that provide a total amount of about 90 mg/m 2 of irinotecan free base, or an amount of irinotecan equivalent to 100 mg/m 2 irinotecan hydrochloride trihydrate.
  • the unit dosage form can be an intravenous formulation obtained by diluting a unit dosage form (e.g., a vial) at a concentration of about 4.3 mg irinotecan free base/ mL injectable fluid into a total volume of about 500 mL.
  • ONIVYDE is prepared for administering by diluting the isotonic liposomal dispersion from the vial as follows: withdraw the calculated volume of ONIVYDE from the vial.
  • ONIVYDE is diluted into 500mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted solution by gentle inversion; protect diluted solution from light and administer diluted solution within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2°C to 8°C (36°F to 46°F)].
  • Example 10 The ability of Nal-IRI to deliver irinotecan and SN-38 to tumors was evaluated in SCLC cell-line derived xenograft (CDX) models (NCI-H1048, DMS-114, H841) in comparison to patient-derived xenograft (PDX) models (CRC, SCLC and pancreatic).
  • Irinotecan liposome injection was administered intravenously to mice bearing xenograft tumors. At 24 hours post administration, mice were sacrificed and tumors were harvested. Irinotecan and SN-38 in tumors were measured by high performance liquid chromatography (HPLC). Data were normalized to injected dose per tumor weight.
  • HPLC high performance liquid chromatography
  • Figure 7A shows the increased tumor SN-38 levels were associated with increased tumor deposition, as assessed by tumor CPT-11 at 24 hours post administration in SCLC mouse xenograft models (H841, HI 048 and DMS-53).
  • Figure 7B shows the carboxylesterase (CES) activity in CRC, SCLC, and pancreatic PDX tumors showing that SCLC PDX tumors have CES activity comparable to other indications in which irinotecan is active.
  • Treatment with SN-38 decreased cell viability by > 90% in SCLC cell lines (DMS 114, NCI-H1048).
  • FIG. 7D is a graph showing cell sensitivity; cytotoxicity of Topol inhibitors increases with exposure.
  • Figure 7E is a chart showing that topotecan administration is severely limited by toxicity, thus limiting sustained inhibition of topol in comparison to Onivyde mediated prolonged SN-38 exposure.
  • Example 11 Preclinical Support for Evaluation of irinotecan liposome injection (nal-IRI, MM-398) in Patients with Small Cell Lung Cancer
  • nal-IRI Anti-tumor activity of nal-IRI as a monotherapy was evaluated in DMS-53 and NCI-H1048 xenograft models.
  • Cells were implanted subcutaneously into right flanks of NOD-SCID mice; treatments were initiated when tumors had reached approximately 280 mm 3 .
  • Nal-IRI was dosed at 16 mg/kg salt, qlw, which is equivalent to a proposed clinical dose of 90 mg/m 2 free base, q2w.
  • Topotecan was dosed at 0.83 mg/kg/week, Day 1-2 every 7 days, which approximates a clinical dose intensity of 1.5 mg/m 2 (Day 1-5 every 21 days).
  • Tumor metabolite levels of nal-IRI and non-liposomal irinotecan were measured at 24 hours post-injection, using previously established high performance liquid chromatography methods.
  • the results for the monotherapy treatment in DMS-53 are shown in Figure 8A and the results in NCI-H1048 are shown in Figure 8B.
  • the vertical dotted lines indicate days of dosing and the response rates are determined based on tumor volume change from base line: CR: change in tumor volume (TV) ⁇ -95%; PR: -95% ⁇ change in TV ⁇ -30%; SD: -30% ⁇ change in TV ⁇ 30%; PD: change in TV > 30%.
  • Nal-IRI displayed significantly greater anti-tumor activity than topotecan based on tumor growth kinetics and overall survival. Furthermore, 7 out of 7 mice in NCI-H1048 model treated with nal-IRI experienced complete tumor regressions after 4 cycles of treatment and maintained for at least 50 days after last dose, compared to 0 out of 7 mice treated with topotecan.
  • Carboxylesterase activity and sensitivity to SN-38 in SCLC models were comparable to that in indications where nal-IRI or irinotecan HC1 has proven to be efficacious clinically (e.g. pancreatic cancer, colorectal cancer).
  • Nal-IRI was found to deliver irinotecan to tumors in SCLC tumors to a similar or greater extent than other tumor types.
  • the tumor irinotecan and SN-38 levels of nal-IRI (16 mg/kg salt) were 12 to 57-fold and 5 to 20-fold higher than nonliposomal irinotecan (30 mg/kg salt), respectively.
  • Nal-IRI demonstrated anti-tumor activity in both xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses after 4 cycles of treatment, compared to topotecan which have limited tumor growth control.
  • FIG. 8C is a graph showing the percent survival of rats treated with control, Onivyde (30 or 50 mg/kg salt), irinotecan (25 mg/kg) or topotecan (4 mg/kg) for days post inoculation. Rats treated with Onivyde at both 30 and 50 mg/kg showed longer survival times that those treated with control, irinotecan or topotecan.
  • MM-398 has anti-tumor activity in multiple SCLC xenograft models. At clinically relevant doses (16 mg/kg/wk MM-398, 0.8 mg/kg/wk topotecan), MM-398 had greater anti-tumor activity and prolonged survival than topotecan.
  • nal-IRI and non-liposomal irinotecan HCl were compared to non-liposomal irinotecan in SCLC tumor bearing xenograft models DMS-53 and NCI-H1048 ( Figures 9A and 9B).
  • the clinically-relevant doses of nal-IRI and non-liposomal irinotecan HCl in mice are approximately 16 mg/kg (salt) and 30 mg/kg (salt), respectively.
  • Nal-IRI dosed at 16 mg/kg salt (qlw) is equivalent to a proposed clinical dose of 90 mg/m 2 free base, q2w.
  • tumor levels of CPT- 1 1 ( Figure 9 A) and the active metabolites SN-38 ( Figure 9B) were measured at 24 hours post-injection (intravenous via tail vein).
  • nal-IRI delivered irinotecan to tumors to a greater extent than non-liposomal irinotecan HCl.
  • the tumor CPT- 1 1 and SN-38 levels of nal-IRI (16 mg/kg salt) were 12 to 57-fold and 5 to 20-fold higher than non-liposomal irinotecan (30 mg/kg salt), respectively.
  • Example 13 Irinotecan Liposome Injection-mediated Tumor Delivery of Irinotecan and SN-38 In Vivo
  • MM-398 The ability of MM-398 to deliver irinotecan and SN-38 to tumors was evaluated in SCLC cell-line derived xenograft (CDX) models (NCI-H1048, DMS-114, H841) in comparison to CDX and patient-derived xenograft (PDX) models of other tumor types.
  • Irinotecan liposome injection was administered intravenously to mice bearing xenograft tumors. At 24 hours post administration, mice were sacrificed and tumors were harvested. Irinotecan and SN-38 in tumors were measured by high performance liquid chromatography (HPLC). Data were normalized to injected dose per tumor weight.
  • tumors derived from SCLC cell lines have similar or higher levels of irinotecan liposome injection deposition, as assessed by irinotecan content, than other tumor types. Furthermore, analysis of SN-38 levels indicates that increased irinotecan delivery was associated with increased levels of SN-38.
  • Example 14 Anti-tumor Activity of Irinotecan Liposome Injection, Non- Liposomal Irinotecan and Topotecan in a Preclinical Model of Second Line SCLC
  • Nal-IRI is designed for extended circulation relative to non-liposomal irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38, in the tumors. Sustained inhibition of
  • TOPI topoisomerase 1
  • mice bearing NCI-H1048 SCLC tumors were treated with a carboplatin plus etoposide, a first line regimen in SCLC. Once the tumors escaped growth control by carboplatin plus etoposide, mice were randomized to either continue treatment with carboplatin plus etoposide or switch to second line treatment with either irinotecan liposome injection, non-liposomal irinotecan or topotecan.
  • mice with NCIH1048 SCLC xenograft tumors were treated weekly with the combination of 30 mg/kg carboplatin plus 25 mg/kg etoposide.
  • Vertical dotted lines indicate start of weekly dosing.
  • carboplatin plus etoposide -treated SCLC tumors Nal-IRI remains active and is trending towards complete response; non-liposomal irinotecan treatment is active but after 3rd cycle some tumors are trending regrowth;
  • Topotecan (at 2x clinically relevant dose) seems to be active after 1-2 cycles but progress quickly after 3rd dose; carboplatin plus etoposide is not tolerable by the 5th cycle.
  • irinotecan liposome injection had anti -turn or activity in the second line setting and, furthermore, had significantly greater anti-tumor activity than both non-liposomal irinotecan and topotecan.
  • Figure 2 IB is a survival graph for mice on each of the treatments.
  • Example 15 Irinotecan Liposome Injection Has Improved Anti-Tumor Activity as Compared to Non-liposomal Irinotecan HC1 and Topotecan in Vivo.
  • Figure 23 presents tumor growth kinetics of mice bearing SCLC xenograft tumors that were treated weekly with irinotecan liposome injection, topotecan and non-liposomal irinotecan (two of the three).
  • irinotecan liposome injection displayed significantly greater anti -tumor activity than both non-liposomal irinotecan and topotecan.
  • irinotecan liposome injection displayed significantly greater anti-tumor activity than did topotecan.
  • 10 out of 10 mice treated in NCI-H1048 model treated with irinotecan liposome injection experienced complete regressions of their tumors as compared to 0 out of 10 mice treated with topotecan.
  • Figure 23 shows the data obtained from NOD/SCID mice with subcutaneous ( Figure 23 A) DMS-53, ( Figure 23B) DMS-114 or ( Figure 23C) NCI-H1048.
  • SCLC xenograft tumors were treated with IV nal-IRI (16 mg/kg; triangles), IV irinotecan (33 mg/kg;
  • IP topotecan (0.83 mg/kg/wk days 1-2; squares) or vehicle control (circles).
  • Vertical dotted lines indicate start of weekly dosing and error bars indicate standard error of the mean.
  • Irinotecan liposome injection dose is shown on irinotecan HC1 basis.
  • irinotecan liposome injection displayed significant anti-tumor activity compared to topotecan (p ⁇ 0.0001 for DMS-114 on day 52 and p ⁇ 0.0001 for NCI-H1048 on day 59; non-parametric t-test) and irinotecan (p ⁇ 0.0001 for DMS-114 on day 65 and p ⁇ 0.0001 for NCI-H1048 on day 84; non-parametric t-test).

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Abstract

La présente invention concerne de nouvelles thérapies pour le traitement du cancer bronchique à petites cellules (CBPC) consistant à administrer un traitement antinéoplasique constitué d'irinotécan liposomal administré une fois toutes deux semaines, comprenant optionnellement l'administration d'autres agents non-antinéoplasiques au patient, par exemple l'administration d'un corticostéroïde et d'un antiémétique au patient avant l'administration du liposome d'irinotécan.
EP17734449.6A 2016-05-18 2017-05-17 Irinotécan nanoliposomal utilisé dans le traitement du cancer bronchique à petites cellules Withdrawn EP3458059A1 (fr)

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CA2992789A1 (fr) 2015-08-20 2017-02-23 Ipsen Biopharm Ltd. Traitement combine utilisant l'irinotecan liposomal et un inhibiteur de parp pour un traitement anticancereux
KR102714060B1 (ko) 2015-08-21 2024-10-08 입센 바이오팜 리미티드 리포솜 이리노테칸 및 옥살리플라틴을 포함하는 병용 치료를 이용하여 전이성 췌장암을 치료하는 방법
MA42991A (fr) 2015-10-16 2018-08-22 Ipsen Biopharm Ltd Stabilisation de compositions pharmaceutiques de camptothécine
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